Pregnancy requires the remodeling of the female reproductive tract from an environment that is hostile to foreign cells into immunologically safe and nurturing surroundings. Such changes are necessary in order to sustain the normal growth and development of the embryo and fetus. The requisite changes in the uterine milieu required for the establishment and maintenance of pregnancy are largely orchestrated by two cell lineages: decidua and trophoblast. Together these highly specialized cells transiently modify the maternal compartment. The vascular is rearranged, immune and inflammatory cells are repositioned, and a selective barrier is created. Under normal circumstances a balance is established resulting in a nurturing environment that provides protection for both mother and fetus. Unfortunately, the consequences of dysregulation are pregnancy termination, intrauterine growth retardation, and/or maternal compromise. This program project focuses on elucidating the nature of vital protective mechanisms that ensure a safe and hospital environment for the fetus to develop within the maternal reproductive tract. The program project grant application is comprised of three key subprojects and two complementary core units. Individual subprojects address: i) uterine decidual cell signaling mechanisms involved in the regulation of maternal uterine inflammatory cells, ii) multidrug resistant efflux systems used by the placenta to protect the fetus, and iii) the impact of soluble placental major histocompatibility complex proteins on maternal inflammatory and immune cell responses. The Administrative and Cell and Tissue Core Units centralize important components of the research activities and will greatly facilitate these efforts. The overall goal of the program project is to understand regulatory processes that will lead to the development of therapeutic strategies for the purpose of improving the quality and success of pregnancy.